Worse Prognosis Research Articles

Preoperative cerebral angiography nearly doubles the rate of diffusion-weighted imaging lesion detection following minimally invasive surgery for intracerebral hemorrhage

BackgroundDiffusion-weighted imaging (DWI) lesions have been linked to poor outcomes after intracerebral hemorrhage (ICH). We aimed to assess the impact of cerebral digital subtraction angiography (DSA) on the presence of...

Neuroanatomical and prognostic associations of depression in Parkinson’s disease

BackgroundDepression is reported as a risk factor, prodromal feature and late consequence of Parkinson’s disease (PD). We aimed to evaluate the timing, neuroanatomy and prognostic implications of depression in PD.MethodsWe...

Management of mild Cervical Spondylotic Myelopathy

Introduction: Most of the elderly individuals with cervical spondylotic myelopathy (CSM) suffer from a progressive, and irreversible spinal cord dysfunction and pain. The incidence is rising in tandem with the ageing population. Due to its debilitating effects on a person's physical, mental, and social aspects, it is quickly becoming a public health issue. Therefore, the primary objective is to diagnose the condition in its milder form, prevent its progression, and treat the symptoms aggressively. This article discusses the management of mild CSM, including our experiences, difficulties, current state of knowledge, and potential future developments. Methodology: From the patients presenting with neck pain in the OPD, those with mild CSM according to modified Japanese Orthopedic Association (mJOA) scoring system were selected. Their disabilities were studies with commonly used scoring systems like Nurick grading, Neck Disability Index (NDI), and quality of life with SF-36v2. Only the degenerative cases were included, and other pathologies were excluded. Classical cervical disc prolapse with radiculopathy was also not included. Conservative management was initiated in all these patients and followed up for the improvement or deterioration. Results: With the above selection criteria, 235 patients with mild CSM were included in the studies. There were 186 males and 49 females with ages ranging from 42 to 78 years. The clinical profiles were studied. The major signs and symptoms were neck pain, disturbed dexterity of hands, imbalance on walking and exaggerated reflexes. The impairments were stratified and found that the average mJOA score was 16.2, Nurick score was 2.8 and NDI was 33.6. The quality of life was judged using SF-36v2 and was 39.7. The patients were monitored for three, six, twelve, and twenty-four months with conservative care. The follow up was very poor and only 46 out of the total 235 patients could be followed up to two years. Thus the result obtained could not derive any significant information. The symptoms like pain significantly reduced and there was improvement in overall scores including the quality of life. There were no case of deterioration during the conservative treatment. Thus, there was no discernible advancement that called for surgery. Conclusion: Mild CSM is a common, under diagnosed and usually ignored entity which affects big portion of elderly population. It specifically impacts the mental and social aspects that impairs one's quality of life, as well as the functional and emotional aspects. They are initially being treated conservatively and closely monitored for signs of worsening and advancement. Most of the patients respond to conservative treatment but those having risk factors for progression and bad prognosis, should remain vigilant of any features of deterioration. The treatment plan must be timely modified if a patient's clinical condition deteriorates preventing life-long sufferings.

Combined DeRitis ratio and alkaline phosphatase on the prediction of portal vein tumor thrombosis in patients with hepatocellular carcinoma

Portal vein tumor thrombosis (PVTT) is one of the common complications of HCC and represents a sign of poor prognosis. PVTT signifies advanced liver cancer, deteriorating liver function, and heightened susceptibility to intrahepatic dissemination, systemic metastasis, and complications related to portal hypertension. It is important to seek novel strategies for PVTT arising from HCC. Portal vein tumor thrombus (PVTT) in hepatocellular carcinoma (HCC) represents a worse liver function, less treatment tolerance, and poor prognosis. This study aimed to investigate the diagnostic value of the combination of the DeRitis ratio (AST/ALT) and alkaline phosphatase (ALP) index (briefly named DALP) in predicting the occurrence risk of PVTT in patients with HCC. We performed a retrospective study enrolling consecutive patients with HCC from January 2017 to December 2020 in Hebei Medical University Third Hospital. ROC analysis was performed to estimate the predictive effectiveness and optimal cut-off value of DALP for PVTT occurrence in patients with HCC. Kaplan–Meier analysis revealed the survival probabilities in each subgroup according to the risk classification of DALP value. Univariate and multivariate Logistics regression analyses were applied to determine the independent risk for poor prognosis. ROC analysis revealed that the optimal cut-off value for DALP was 1.045, with an area under the curve (AUC) of 0.793 (95% CI 0.697–0.888). Based on the DALP classification (three scores: 0–2) with distinguishable prognoses, patients in the score 0 group had the best prognosis with a 1-year overall survival (OS) of 100%, whereas score 2 patients had the worst prognosis with 1-year OS of 72.4%. Similarly, there was a statistically different recurrence-free survival among the three groups. Besides, this risk classification was also associated with PVTT progression in HCC patients (odds ratio [OR] 5.822, P < 0.0001). Pathologically, patients in the score 2 group had more advanced tumors considering PVTT, extrahepatic metastasis, and ascites than those in score 0, 1 groups. Moreover, patients with a score of 2 had more severe hepatic inflammation than other groups. Combination of DeRitis ratio and ALP index presented a better predictive value for PVTT occurrence in patients with HCC, contributing to the tertiary prevention.

Clinicopathological characteristics and genetic features of young and senior Ewing sarcoma patients

BackgroundEwing sarcoma (EwS) is a highly malignant and heterogeneous tumor. Exploring clinicopathological characteristics and genetic features of EwS is critical for prognosis and treatment regimen.MethodsClinicopathological characteristics and genetic features of young (≤ 30y) and senior (> 30y) EwS patients were analyzed based on histology, phenotype, and next-generation sequencing (NGS) detection.ResultsThe young group (18/36) presented nontypical EwS histological morphology, whereas the senior group (18/36) presented typical morphology. The prognosis of the young group was found to be worse compared with the senior group for patients without metastasis at the initial diagnosis. DNA- and RNA-based NGS was conducted on 20 extraosseous EwS patients. 16/20 samples demonstrated EWSR1-FLI1 fusion and 4/20 demonstrated EWSR1-ERG fusion. However, 13/16 EWSR1-FLI1fusions were detected both in DNA- and RNA-based NGS, 1/16 was detected only at the DNA level, and 2/16 were detected only at the RNA level. An analysis of the genetic profiles of the EWSR1-FLI1 cases revealed that the young group was inclined to couple with more copy number variations (CNV), such as CCND1, CDK4 amplification, and fusion variations, such as CHEK1-EWSR1, SLIT2-EWSR1, and EWSR1-FAM76B fusion. The senior group was more likely to have SNV or Indel mutations, such as EPHA3 and STAG2 mutations. Moreover, patients with more CNV abnormalities had a worse prognosis than those with predominantly SNP variants. In addition, compared with the senior group, the young group had significantly higher CyclinD1 protein expression.ConclusionClinicopathological characteristics and genetic features in young and senior EwS patients differed significantly. Targeting cell cycle dysregulation based on age subgroup may be a potential therapeutic strategy for Ewing sarcoma.

Cellular and extracellular proteomic profiling of paradoxical low-flow low-gradient aortic stenosis myocardium.

Patients with severe aortic stenosis (AS), low transvalvular flow (LF) and low gradient (LG) with normal ejection fraction (EF)-are referred to as paradoxical LF-LG AS (PLF-LG). PLF-LG patients develop more advanced heart failure symptoms and have a worse prognosis than patients with normal EF and high-gradient AS (NEF-HG). Despite its clinical relevance, the mechanisms underlying PLF-LG are still poorly understood. Left ventricular (LV) myocardial biopsies of PLF-LG (n = 5) and NEF-HG patients (n = 6), obtained during transcatheter aortic valve implantation, were analyzed by LC-MS/MS after sequential extraction of cellular and extracellular matrix (ECM) proteins using a three-step extraction method. Proteomic data are available via ProteomeXchange with identifier PXD055391. 73 cellular proteins were differentially abundant between the 2 groups. Among these, a network of proteins related to muscle contraction and arrhythmogenic cardiomyopathy (e.g., cTnI, FKBP1A and CACNA2D1) was found in PLF-LG. Extracellularly, upregulated proteins in PLF-LG were related to ATP synthesis and oxidative phosphorylation (e.g., ATP5PF, COX5B and UQCRB). Interestingly, we observed a 1.3-fold increase in cyclophilin A (CyPA), proinflammatory cytokine, in the extracellular extracts of PLF-LG AS patients (p < 0.05). Consistently, immunohistochemical analysis confirmed its extracellular localization in PLF-LG AS LV sections along with an increase in its receptor, CD147, compared to the NEF-HG AS patients. Levels of core ECM proteins, namely collagens and proteoglycans, were comparable between groups. Our study pinpointed novel candidates and processes with potential relevance in the pathophysiology of PLF-LG. The role of CyPA in particular warrants further investigation.

Abstract PR-16: Evaluating direct KRASQ61H inhibition in pancreatic cancer models

Abstract KRASQ61 mutations are associated with the worst prognosis among the various KRAS mutational subtypes of pancreatic ductal adenocarcinoma (PDAC). RMC-7977 is a RAS(ON) multi-selective noncovalent inhibitor with broad spectrum activity against oncogenic RAS mutants and wild-type RAS. The related investigational agent RMC-6236 is currently undergoing clinical trials. Binary complexes of CypA: RMC-7977 bind equipotently to multiple KRAS mutational subtypes however RMC-7977 is less potent at inhibiting growth in KRASQ61H-mutant cell lines. In contrast, RM-047 is a preclinical RAS(ON) Q61H-selective inhibitor tool compound. We evaluated direct KRASQ61H inhibition using both RMC-7977 and RM-047 in cell culture models. We found that in KRASQ61H-rescued RASless mouse embryonic fibroblasts (MEFs), RM-047 inhibited ERK activity and suppressed growth more potently than RMC-7977. Conversely, in a panel of KRASQ61H-mutant PDAC cell lines, RM-047 was less potent than RMC-7977 in two out of three KRASQ61H-mutant PDAC cell lines. Furthermore, we discovered that ERK activity rapidly rebounded with treatment in KRASQ61H-mutant PDAC cell lines, whereas ERK activity remained suppressed in KRASQ61H-rescued RASless MEFS lacking WT RAS alleles. Our analysis of DepMap data indicated that among the KRAS mutational subtypes frequently found in pancreatic cancer, KRASQ61H is the least dependent on KRAS for survival. This suggests that in a KRASQ61H-mutant PDAC setting, additional factors such as WT RAS expression may mediate growth. From our KRAS drug-anchored CRISPR loss-of-function screens, we found that the loss of EGFR sensitized cells to KRAS inhibition, particularly in a KRASQ61H-dependent context. Therefore, we combined erlotinib, an FDA-approved EGFR inhibitor, with either RM-047 or RMC-7977, and found that the addition of erlotinib prevented ERK rebound activity and synergized with RM-047 or RMC-7977 to reduce growth in KRASQ61H-mutant PDAC cell lines. These data provide insights into mechanisms by which KRASQ61H-mutant PDAC may be less dependent on KRAS for survival and further support the clinical evaluation of combined EGFR and RAS(ON) inhibition as a potential therapeutic strategy in the treatment of PDAC patients harboring KRASQ61H mutations. Citation Format: Szu-Aun Long, Amber M Amparo, Haley Todd, Grace Goodhart, Syed A Ahmad, Andrew M Waters. Evaluating direct KRAS inhibition in pancreatic cancer models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-16.

Abstract A035: 3D High-Density Collagen I Improves the Modeling of Aggressive Pancreatic Cancer

Abstract Background: Fibrillar collagen type I constitutes the majority of the extracellular matrix in pancreatic ductal adenocarcinoma (PDAC), yet most in vivo murine models involve the use of basement membrane extracts, which instead contain collagen type IV, as matrices to embed PDAC cells. Type I collagen in the PDAC tumor microenvironment has been associated with worse prognosis. Our hypothesis is that PDAC cells grown in 3D high-density collagen I (HDC) gels behave more aggressively compared to the same cells grown using conventional basement membrane matrix (BMM). Methods: The KPC1199 2D cell line was previously generated from a tumor-bearing male KPC mouse. KPC1199 cells were cultured in vitro in HDC or BMM for one week. Orthotopic tumors were established by embedding KPC1199 cells in HDC (N=10) or BMM (N=10) in the pancreatic tail of syngeneic C57BL/6J mice via laparotomy. Half of the tumors were collected five weeks after tumor implantation, and the other half utilized for a survival study. Collagen was imaged by second harmonic generation (SHG) microscopy. Results: In vitro imaging of single KPC1199 cells grown in HDC revealed an aggressive phenotype with clonal network-like structures compared to a spheroidal, non-aggressive phenotype for cells grown in BMM over the course of seven days. SHG imaging confirmed consistent formation and organization of collagen in HDC tumors but minimal to faint collagen formation in BMM tumors. Gross examination of HDC mice showed 60% with visible liver metastasis compared with none in the BMM mice. In the survival study, the entire HDC group died before the BMM group (p-value &amp;lt; 0.01). Conclusions: Our pilot study is the first, to our knowledge, to successfully generate orthotopic PDAC tumors using 3D high-density collagen I in a mouse model. KPC1199 cells embedded in HDC showed an aggressive phenotype in vitro, and resultant tumors demonstrated more robust collagen organization compared to the same cells grown in the BMM substrate. This aggressive phenotype translated to visible liver metastasis within five weeks in the HDC mice and prior to death from primary tumor burden. This is not typical for most KPC-derived cell lines but is typical for human PDAC patients. Our preliminary findings support the use of HDC as an alternative substrate for better modeling of this aggressive cancer. Citation Format: Kim Nguyen-Ta, Sural Ranamukhaarachchi, Jeffrey Turner, Utsav Joshi, Himangshu Sonowal, Jorge de la Torre Medina, Herve Tiriac, Stephanie Fraley, Rebekah White. 3D High-Density Collagen I Improves the Modeling of Aggressive Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A035.

Abstract C011: Targeting STAT3 overcomes PDAC resistance to EGFR/RAF1 inhibition leading to complete and durable tumor regression

Abstract Pancreatic ductal adenocarcinoma (PDAC) belongs to the tumors with worst prognosis due to the lack of effective treatment. It was previously demonstrated that combined elimination of EGFR and RAF1, two main mediators of the KRAS signaling, induces complete regression of a limited subset of small tumors in a genetically engineered mouse model (Blasco et al., 2019). In the current study, we show that resistance of PDACs with big sizes to the elimination of RAF1 and EGFR is mediated by STAT3. Indeed, combined genetic ablation of EGFR, RAF1 and STAT3 both in vitro and in vivo, results in complete and irreversible regression of more than 40 independent mouse PDAC tumors driven by Kras/Trp53 mutations. Importantly, all PDACs were characterized by increased initial tumor size and highly heterogeneous molecular profile similar to that of Basal human tumors. Moreover, we have validated the efficacy of this novel therapeutic strategy using pharmacological agents, such as EGFR inhibitors approved for clinical use and the STAT3 PROTAC degrader SD-36. Finally, inhibition of RAF1, EGFR and STAT3 expression effectively blocked in vitro and in vivo tumor progression in ten independent patient-derived organoid (PDO) and patient-derived xenograft (PDX) cultures carrying KRAS and TP53 mutations. These results open the door to the development of novel targeted therapies for PDAC patients. Citation Format: Vasiliki Liaki, Mariano Barbacid, Carmen Guerra. Targeting STAT3 overcomes PDAC resistance to EGFR/RAF1 inhibition leading to complete and durable tumor regression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C011.

Abstract B040: B cells facilitate lymph node colonization in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) carries a low survival rate. Several factors contribute to its dismal prognosis, including resistance to available therapies and high invasiveness. Lymph nodes act as an early systemic source of circulating malignant cells, allowing their dissemination to other organs early in disease progression. Lymphatic colonization is linked to worse prognosis, and a better understanding of mechanisms regulating lymph node metastasis is clinically needed. To study each step in the metastatic cascade to the lymph nodes, we have developed a mouse co-clinical model of resectable pancreatic cancer. This model mimics the frequency of human PDAC metastatic recurrence, on a similar time scale relative to the lifespans of mice and humans and allows us to investigate very early events in the metastatic cascade. In contrast to the established anti-tumor role of T cells, the role of B cells in cancer immunology is more complex. B cells are a predominant immune population in lymph nodes, but their role in relation to lymph node colonization has never been fully addressed. Using our model of PDAC spontaneous metastasis and a mouse model of B cell depletion, we showed that lymph node metastasis does not form in the absence of B cells. We demonstrated that B cells, but not secreted antibodies, are required for successful lymph node colonization. We also gained evidence that B cells are orchestrating a complex interplay between disseminated cancer cells and other immune cells in the draining lymph node. Particularly, T cells seem to be involved in preventing cancer cell from growing into macro-metastasis only in the absence of B cells. We are now investigating the mechanisms employed by B cells to facilitate this cellular network to facilitate lymph node colonization in PDAC. The ultimate outcome of our work will be the design of effective immune strategies to prevent and treat lymph node dissemination of such a deadly disease. Citation Format: Alice Bertocchi, Megan T Hoffman, Li Qiang, Massiel Morell, Lauren L Hsu, Michael L Dougan, Judith Agudo, Stephanie K Dougan. B cells facilitate lymph node colonization in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B040.

Comparisons of clinical characteristics, treatments, and outcomes among different pathological subtypes of chondrosarcoma in the spine.

Spinal chondrosarcoma exhibits higher invasiveness and a worse prognosis compared to chondrosarcoma in the extremities. The prognosis and therapeutic plan vary greatly among different pathological subtypes of chondrosarcoma. This study aimed to analyze the differences in clinical characteristics, molecular features, therapeutic effects, and prognostic factors among the subtypes of chondrosarcoma in the spine. A retrospective review was conducted on 205 patients with spinal chondrosarcoma. The clinical features and immunohistochemical (IHC) markers were compared among the pathological subtypes of chondrosarcoma grade 1, grade 2, grade 3, mesenchymal chondrosarcoma (MCS), dedifferentiated chondrosarcoma (DCS), and clear cell chondrosarcoma (CCCS). Chondrosarcoma grade 1/2/3 are collectively referred to as conventional chondrosarcoma (CCS) for multivariate survival analysis. Univariate and multivariate analyses were performed to investigate independent prognostic factors for overall survival (OS) and recurrence-free survival (RFS) in patients with spinal chondrosarcoma. Furthermore, independent prognostic factors for OS and RFS were identified in CCS and MCS. MCS patients were younger than the other subtypes. Patients with chondrosarcoma grade 1/2 had better OS than those with chondrosarcoma grade 3, MCS and DCS, while only chondrosarcoma grade 1 patients showed better RFS than chondrosarcoma grade 2/3, MCS and DCS patients. Ki-67 index was higher in chondrosarcoma grade 3, MCS and DCS than chondrosarcoma grade 1/2. The comparison of IHC markers further highlighted the overexpression of P53/MDM2 in MCS and DCS. Gross total resection, including en-bloc and piecemeal resection, significantly improved OS and RFS for CCS patients, while only en-bloc resection significantly improved the prognosis of MCS patients. Chemotherapy appeared to be important for the OS of MCS patients. P53/MDM2 pathway was upregulated in MCS and DCS compared to chondrosarcoma grade 1/2. Radical tumor resection is crucial for the treatment of spinal chondrosarcoma, while MCS patients require further comprehensive treatments perioperatively.

Recruitment of USP10 by GCS1 to deubiquitinate GRP78 promotes the progression of colorectal cancer via alleviating endoplasmic reticulum stress

BackgroundLong-term accumulation of misfolded proteins leads to endoplasmic reticulum (ER) stress in colorectal cancer (CRC). However, the precise pathways controlling the decision between survival and apoptosis in CRC are unclear. Therefore, in this study, we investigated the function and molecular mechanism of glucosidase I (GCS1) in regulating ER stress in CRC.MethodsA public database was used to confirm the expression level of GCS1 in CRC and normal tissues. Clinical samples from our center were used to confirm the mRNA and protein expression levels of GCS1. Cell proliferation, migration, invasion, and apoptosis assays revealed the biological role of GCS1. Immunohistochemical techniques were used to evaluate the expression of key proteins in subcutaneous implanted tumors in nude mice, which provided further evidence for the biological function of GCS1 in promoting cancer in vivo. The results of coimmunoprecipitation-mass spectrometry analysis and immunofluorescence colocalization analysis the interaction between GCS1 and GRP78. In addition, the mechanism of action of USP10, GRP78, and GCS1 at the post- translational level was investigated. Finally, a tissue microarray was used to examine the connection between GCS1 and GRP78 expression and intracellular localization of these proteins using immunohistochemistry and immunofluorescence.ResultsThe experimental results revealed that GCS1 was substantially expressed in CRC, with higher expression indicating a worse prognosis. Thus, GCS1 can enhance the proliferation and metastasis while inhibiting the apoptosis of CRC cells both in vivo and in vitro. Mechanistically, GCS1 binds to GRP78, recruits USP10 for deubiquitination of GRP78 to promote its degradation, and decreases ER stress-mediated apoptosis, increasing CRC cell proliferation and metastasis.ConclusionsIn summary, GCS1 stimulates CRC growth and migration and reduces ER stress-mediated apoptosis via USP10-mediated deubiquitination of GRP78. Our findings identify a possible therapeutic target for CRC.

Long-read transcriptome sequencing of CLL and MDS patients uncovers molecular effects of SF3B1 mutations.

Mutations in splicing factor 3B subunit 1 (SF3B1) frequently occur in patients with chronic lymphocytic leukemia (CLL) and myelodysplastic syndromes (MDS). These mutations have different effects on the disease prognosis with beneficial effect in MDS and worse prognosis in CLL patients. A full-length transcriptome approach can expand our knowledge on SF3B1 mutation effects on RNA splicing and its contribution to patient survival and treatment options. We applied long-read transcriptome sequencing (LRTS) to 44 MDS and CLL patients, as well as two pairs of isogenic cell lines with and without SF3B1 mutations, and found >60% of novel isoforms. Splicing alterations were largely shared between cancer types and specifically affected the usage of introns and 3' splice sites. Our data highlighted a constrained window at canonical 3' splice sites in which dynamic splice site switches occurred in SF3B1-mutated patients. Using transcriptome-wide RNA binding maps and molecular dynamics simulations, we showed multimodal SF3B1 binding at 3' splice sites and predicted reduced RNA binding at the second binding pocket of SF3B1K700E Our work presents the hitherto most complete LRTS study of the SF3B1 mutation in CLL and MDS and provides a resource to study aberrant splicing in cancer. Moreover, we showed that different disease prognosis most likely results from the different cell types expanded during carcinogenesis rather than different mechanisms of action of the mutated SF3B1 These results have important implications for understanding the role of SF3B1 mutations in hematological malignancies and other related diseases.

Potential application of [18F]AlF-PSMA-11 PET/CT in radioiodine refractory thyroid carcinoma

BackgroundPatients diagnosed with radioiodine refractory (RAI-R) thyroid carcinoma (TC) have a significantly worse prognosis than patients with radiosensitive TC. These refractory malignancies are often dedifferentiated, hindering the effectiveness of iodine-based imaging. Additionally, the role of metabolic imaging using [18F]FDG PET/CT is also limited in these cases, making adequate staging of RAI-R TC challenging. Recent case series have shown promising results regarding the role of the prostate-specific membrane antigen (PSMA) in TC. In this study we explored the value of [18F]AlF-PSMA-11 PET/CT in RAI-R TC.MethodsIn this phase II study, lesions detected on [18F]AlF-PSMA-11 PET were compared to findings from [18F]FDG PET/CT. Additionally, the serologic soluble prostate-specific membrane antigen (sPSMA) was measured using ELISA. PSMA-expression on tumor tissue in any available resection specimens was analysed with an immunostainer.ResultsEight patients were included, with a total of 39 identified lesions based on PET imaging. [18F]AlF-PSMA-11 PET identified 30 of 39 lesions, and [18F]FDG PET identified 33 lesions, leading to a detection rate of 76.9% and 84.6%, respectively. Interestingly, while nine lesions were solely visualized on [18F]FDG, six were uniquely seen on [18F]AlF-PSMA-11 PET. While sPSMA was immeasurable in all female patients, no correlation was found between sPSMA in male patients and disease-related factors. In five out of eight patients immunohistology showed PSMA expression on the primary tumor.ConclusionsAlthough not all lesions could be visualized, [18F]PSMA-11 PET identified multiple lesions imperceptible on [18F]FDG PET. These results display the potential additional diagnostic role of PSMA-targeted imaging in patients with RAI-R TC.Trial registration number No. EudraCT 2021-000456-19.

Prognostic impact of nectin-like molecule-5 (CD155) expression in non-small cell lung cancer

BackgroundCD155 is a transmembrane protein that inhibits antitumor immune response and represents a predictor of worse prognosis in non-small-cell lung cancer (NSCLC). However, it remains unexplored its association with clinical characteristics and genomic status of Latin American patients. This study characterizes the CD155 expression and its clinical implications in this population.MethodsTissue biopsies from 86 patients with locally-advanced or metastatic NSCLC were assessed for CD155 protein expression, ALK rearrangements and EGFR mutations. Cutoff values for high CD155 expression (CD155high) were determined from receiver operating characteristic (ROC) curves according to 2-year survival. It was evaluated its association with clinicopathological features, median progression-free survival (mPFS) and overall survival (mOS).Resultsthe cutoff score for CD155high was 155 in the entire cohort and in patients without oncogenic alterations, and it was 110 in patients with oncogenic alterations. Eighty-four patients (97.7%) were CD155 positive, of which fifty-six (65.0%) had CD155high. EGFR L858R mutation related to lower CD155 IHC score than exon 19 deletion. Individuals with CD155high showed a shorter mOS (13.0 vs. 30.8 months; HR: 1.96 [95% CI, 1.15–3.35]; p = 0.014). Patients without oncogenic alterations having a CD155high displayed shorter mPFS (1.6 vs. 6.4 months, HR: 2.09 [95% CI, 1.06–4.20]; p = 0.034) and mOS (2.9 vs. 23.1 months; HR: 1.27 [95% CI, 1.07– 4.42]; p = 0.032). Patients with oncogenic alterations having CD155high only showed a trend to shorter mOS (26.3 vs. 52.0 months; HR: 2.39 [95% CI, 0.98–5.83]; p = 0.058).ConclusionCD155high is a predictor of worse outcomes in patients with advanced NSCLC, predominantly among those without oncogenic alterations. CD155 could be a potential biomarker and a molecular target in patients with poor responses to current therapies.

Lymphopenia associated with whole-brain radiotherapy and its effects on clinical outcomes of patients with brain metastases

There is increasing awareness of radiotherapy’s potential side effects, such as lymphopenia. Therefore, this study aimed to establish the association between WBRT and the development of lymphopenia in patients with brain metastases undergoing brain radiotherapy (RT), along with evaluating the corresponding clinical outcomes. Including 116 patients with brain metastases undergoing brain radiotherapy, the study collected the absolute lymphocyte counts (ALC) within 2 weeks before brain radiotherapy (pre-radiotherapy, pre-RT), as well as ones at 1 and 2 months after completing RT (post-RT). Univariate and multivariate analyses were performed to identify associations between radiation modality and post-RT ALC. The relationships between post-RT ALC and overall survival were evaluated with Kaplan–Meier analysis and a multivariate Cox regression model. The median ALC definitely decreased at 1 month post-RT, but at 2 months post-RT, gradually rose but not to the pre-RT ALC. The multivariate analysis identified WBRT and lower pre-RT ALC as independent risk factors associated with the decrease in post-RT ALC at 1 month. It also revealed more than 4 brain metastases, G3-4 lymphopenia at 1 month and lower post-RT ALC at 2 months exhibited significantly worse prognosis regardless of the radiation modality. However, there was indeed an independent correlation between radiation modality and the outcome of intracranial progression-free survival (PFS). To approach the feasibility and reasonableness of treatment, clinicians should carefully consider various factors to achieve long-term survival of patients.

As a novel prognostic model for breast cancer, the identification and validation of telomere-related long noncoding RNA signatures

BackgroundTelomeres are a critical component of chromosome integrity and are essential to the development of cancer and cellular senescence. The regulation of breast cancer by telomere-associated lncRNAs is not fully known, though. The goals of this study were to describe predictive telomere-related LncRNAs (TRL) in breast cancer and look into any possible biological roles for these RNAs.MethodsWe obtained RNA-seq data, pertinent clinical data, and a list of telomere-associated genes from the cancer genome atlas and telomere gene database, respectively. We subjected differentially expressed TRLs to co-expression analysis and univariate Cox analysis to identify a prognostic TRL. Using LASSO regression analysis, we built a prognostic model with 14 TRLs. The accuracy of the model’s prognostic predictions was evaluated through the utilization of Kaplan-Meier (K-M) analysis as well as receiver operating characteristic (ROC) curve analysis. Additionally, immunological infiltration and immune drug prediction were done using this model. Patients with breast cancer were divided into two subgroups using cluster analysis, with the latter analyzed further for variations in response to immunotherapy, immune infiltration, and overall survival, and finally, the expression of 14-LncRNAs was validated by RT-PCR.ResultsWe developed a risk model for the 14-TRL, and we used ROC curves to demonstrate how accurate the model is. The model may be a standalone prognostic predictor for patients with breast cancer, according to COX regression analysis. The immune infiltration and immunotherapy results indicated that the high-risk group had a low level of PD-1 sensitivity and a high number of macrophages infiltrating. In addition, we’ve discovered a number of small-molecule medicines with considerable for use in treating high-risk groups. The cluster 2 subtype showed the highest immune infiltration, the highest immune checkpoint expression, and the worst prognosis among the two subtypes defined by cluster analysis, which requires more attention and treatment.ConclusionAs a possible biomarker, the proposed 14-TRL signature could be utilized to evaluate clinical outcomes and treatment efficacy in breast cancer patients.

Dermatofibrosarcoma Protuberans: An Updated Review of the Literature.

Dermatofibrosarcoma protuberans (DFSP) is a rare proliferative condition representing skin sarcomas which is known to locally recur yet very rarely metastasizes. Its genetic background is a reciprocal translocation t(17;22)(q22;q13) that produces COL1A1-PDGFB gene fusion. Complete resection is the primary treatment. The aim of this review is to outline the pathogenesis, diagnosis, and management of DFSP. A clear-cut distinction between low-to-moderate-grade DFSP with excellent prognosis and high-grade fibrosarcomatous DFSP with a much worse prognosis is underlined. Malignant transformation within DFSP (or high histologic grade), older age, being female, large primary tumor size (≥10 cm), narrow surgical margins of excision (<3 cm), surgical margin positivity for tumor cells, short time to recurrence, numerous recurrences, tumor that was recently rapidly enlarging, and presence of pain in the tumor have all been proposed as clinicopathological risk factors for recurrence and metastasis. A tendency for local growth and local relapses of well- and moderately differentiated DFSPs is an argument for their surgical excision, possibly combined with reconstructive surgery, even in patients of advanced age. Another main point of this review is that cases of DFSP with fibrosarcomatous transformation are a challenge and require careful medical attention. Both anatomopathological evaluation of the presence of lymphovascular space invasion and sentinel lymph node biopsy at DFSP surgery merit further study.

Construction and validation of a TAMRGs prognostic signature for gliomas by integrated analysis of scRNA and bulk RNA sequencing data

BackgroundThis study aimed to construct and validate a prognostic model based on tumor associated macrophage-related genes (TAMRGs) by integrating single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) data. MethodsThe scRNA-seq data of three inhouse glioma tissues were used to identify the tumor-associated macrophages (TAMs) marker genes, the DEGs from the The Cancer Genome Atlas (TCGA) − Genotype-Tissue Expression (GTEx) dataset were used to further select TAMs marker genes. Subsequently, a TAMRG-score was constructed by Least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis in the TCGA dataset and validated in the Chinese Glioma Genome Atlas (CGGA) dataset. ResultsWe identified 186 TAMs marker genes, and a total of 6 optimal prognostic genes including CKS2, LITAF, CTSB, TWISTNB, PPIF and G0S2 were selected to construct a TAMRG-score. The high TAMRG-score was significantly associated with worse prognosis (log-rank test, P<0.001). Moreover, the TAMRG-score outperformed the other three models with AUC of 0.808. Immune cell infiltration, TME scores, immune checkpoints, TMB and drug susceptibility were significantly different between TAMRG-score groups. In addition, a nomogram were constructed by combing the TAMRG-score and clinical information (Age, Grade, IDH mutation and 1p19q codeletion) to predict the survival of glioma patients with AUC of 0.909 for 1-year survival. ConclusionThe high TAMRG-score group was associated with a poor prognosis. A nomogram by incorporating TMARG-score could precisely predict glioma survival, and provide evidence for personalized treatment of glioma.

CD276 as a promising diagnostic and prognostic biomarker for bladder cancer through bioinformatics and clinical research.

To assess CD276 expression and explore its relationship with the clinicopathological characteristics and prognosis of patients with bladder cancer. In total, RNA-sequencing data and clinical profiles of 436 bladder cancer cases from The Cancer Genome Atlas (TCGA) were assessed using the University of California Santa Cruz Xena (UCSC) platform. We compared the CD276 levels in cancerous and adjacent normal tissues and used the R software for statistical association with the clinical stage, grade, and survival (the overall survival, disease-specific survival, and progression-free survival). A single-gene GSEA analysis on TCGA-BLCA data was performed to explore potential pathways through which CD276 might influence bladder cancer. Additionally, CD276 expression was analyzed by comparing data from 9 cancerous tissues and 3 adjacent normal tissues in the GEO dataset GSE7476. Furthermore, we analyzed 133 cancerous bladder and adjacent tissue samples from the Soochow University Hospital, collected between January 1, 2016, and September 30, 2022, to assess the CD276 protein expression using immunohistochemistry. We examined the relationship between tumor CD276 levels and clinical outcomes and prognosis of bladder cancer. Bioinformatic analysis revealed elevated CD276 expression in tumors compared to that in adjacent tissues (p<0.05), correlating with poor survival. GSEA revealed that CD276 was significantly involved in extracellular matrix-related pathways. Immunohistochemistry confirmed CD276 overexpression in tumor tissues, with higher levels linked to advanced pathological grades and worse prognosis. CD276 is markedly upregulated in bladder cancer and associated with severe pathological features, advanced disease, potential for metastasis, and diminished survival rates. It may promote bladder cancer development and progression by influencing extracellular matrix-related-related pathways, making it a viable diagnostic and prognostic biomarker for bladder cancer.